ATORVASTİN VE ROSUVASTATİNİN NEDEN OLDUĞU MİYOPATİYE KARŞI KAFEİK ASİD FENETİL ESTERİN KORUYUCU ETKİSİ
Abstract
AMAÇ: Statinlerin bazı hastalarda myopatiye yol açması nedeni ile hastanın tedaviye uyumu azalmakta, ilacın kullanılmasına son verilmekte veya kullanılan ilaç değiştirilmektedir. Bu çalışmada statinlerin myopatiye neden olabileceği iki durum olarak oksidatif stress ve inflamasyon üzerinde çalışılmış ve Kafeik asit fenil ester (CAPE)’in koruyucu rolü deneysel olarak test edilmiştir.
GEREÇ VE YÖNTEM: Çalışmada rabdomiyosarkom (RD) hücre hatları kullanılmıştır. Hücreler kontrol, atorvastatin, rosuvastatin, CAPE, atorvastatin+CAPE ve rosuvastatin+CAPE olmak üzere 6 gruba ayrılmıştır. Spektrofotometrik olarak Total Antioksidan Kapasite (TAC), Total Oksidan Kapasite (TOC) ve Oksidatif Stres İndeksi (OSI) analizleri yapılmış; İnterlökin 6 (IL-6) düzeyleri hem protein düzeyinde hem de real time PCR ile mRNA ekpresyonu düzeyinde gösterilmiştir.
BULGULAR: Kontrol grubunda 1739 olan OSI atorvastatin uygulaması ile 3814’e çıkmış, atorvastatinin CAPE ile kombinasyonu sonucunda ise 2109’a inmiştir. Rosuvastatin ve Rosuvastatinin CAPE ile kombinasyonu sonucunda kontrol grubuna göre OSI bakımından bir değişiklik olmamıştır. Atorvastin grubunda IL-6 mRNA ekspresyon düzeyleri kontrol grubuna benzer bulunurken, Rosuvastatin grubunda kontrol grubuna nazaran 2,369 kat artış gözlenmiştir. Rosuvastatinin CAPE ile kombinasyonu neticesinde IL-6 mRNA ekspresyon düzeylerinin kontrol grubu seviyesine çekildiği tespit edilmiştir.
SONUÇ: Bu çalışmada Atorvastatinin RD hücre hatlarında oksidatif stresi tetiklediği, rosuvastatinin ise IL -6 mRNA ekspresyon düzeyini artırarak proinflamasyona giden sürecin önünü açtığı gözlemlenmiştir. Atorvastatinin neden olduğu oksitadif stresin ve rosuvastatinin neden olduğu inflamasyonun baskılanmasında CAPE kombinasyonunun işlevsel olduğu tespit edilmiştir. Bu bakımdan tedavide atorvastatin ve rosuvastatinin CAPE ile kombinasyonunun statinlerin neden olduğu kas hasarı üzerine hasta yararına olumlu sonuçlarının olabileceği gösterilmiştir.
Supporting Institution
Gazi Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi
Project Number
TDK-2021-7117
Thanks
Bu çalışma Gazi Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi tarafından TDK-2021-7117 proje numarası ile desteklenmiştir.
References
- 1. Stroes ES, Thompson PD, Corsini A, et al. European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012-22.
- 2. Nielsen SF, Nordestgaard BG. Statin use before diabetes and risk of microvascular disease: a nation wide nested matched study. Lancet Diabet Endocrinol. 2014;2:894-900.
- 3. Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-relatedmortality. N Engl J Med. 2012;367:1792-802.
- 4. Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137:581–5.
- 5. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundamental & Clinical Pharmacology. 2005;19:117-25.
- 6. Du Souich P, Roederer G, Dufour R. Myotoxicity of statins: Mechanism of action. Pharmacol Ther. 2017;175:1-16.
- 7. Zhang P, Tang Y, Li NG, Zhu Y, Duan JA. Bioactivity and chemical synthesis of caffeic acid phenethyl ester and its derivatives. Molecules. 2014;19(10):16458-76.
- 8. Li D, Wang X, Huang Q, Li S, et al. Cardioprotection of CAPE-oNO 2 against myocardial ischemia/reperfusion induced ROS generation via regulating the SIRT1/eNOS/NF-κB pathway in vivo and in vitro. Redox Biol. 2018;15:62-73.
- 9. Parlakpinar H, Sahna E, Acet A, Mizrak B, Polat A. Protective effect of caffeic acid phenethyl ester (CAPE) on myocardial ischemia-reperfusion-induced apoptotic cell death. Toxicology. 2005;209(1):1-14.
- 10. Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods. 1983;65:55–63.
- 11. Erel Ö. A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem. 2004;37(2):112-9.
- 12. Erel Ö. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005;38(12):1103-11.
- 13. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29(9):45.
- 14. Akgun B, Ozturk S, Artas G, Erol FS. Effects of Intrathecal Caffeic Acid Phenethyl Ester (CAPE) on IL-6 and TNF-α Levels and Local Inflammatory Responses in Spinal Cord Injuries. Turk Neurosurg. 2018;28(4):625-9.
- 15. Yiğit U, Kırzıoğlu FY, Uğuz AC, Nazıroğlu M, Özmen Ö. Is caffeic acid phenethyl ester more protective than doxycycline in experimental periodontitis? Arch Oral Biol. 2017;81:61-8.
- 16. Gazzerro P, Proto MC, Gangemi G, et al. Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol Rev. 2012;64(1):102-46.
- 17. Tomaszewski M, Stępień KM, Tomaszewska J, Czuczwar SJ. Statin-induced myopathies. Pharmacol Rep. 2011;63(4):859-66.
- 18. Bouitbir J, Charles AL, Echaniz-Laguna A, et al. Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a 'mitohormesis' mechanism involving reactive oxygen species and PGC-1. Eur Heart J. 2012;33(11):1397-407.
- 19. Kilit C, Koçak FE, Kilit TP. Comparison of the effects of high-dose atorvastatin and high-dose rosuvastatin on oxidative stress in patients with acute myocardial infarction: A pilot study. Turk Kardiyol Dern Ars. 2017;45(3): 235-43.
- 20. Koksal M, Eren MA, Turan MN, Sabuncu T. The effects of atorvastatin and rosuvastatin on oxidative stress in diabetic patients. Eur J Intern Med. 2011;22(3):249-53.
- 21. Yang RL, Shi YH, Hao G, et al. Increasing Oxidative Stress with Progressive Hyperlipidemia in Human: Relation between Malondialdehyde and Atherogenic Index. J Clin Biochem Nutr. 2008;43(3):154-8.
- 22. Klafke JZ, da Silva MA, Panigas TF, et al. Effects of Campomanesia xanthocarpa on biochemical, hematological and oxidative stress parameters in hypercholesterolemic patients. J Ethnopharmacol. 2010;127(2):299-305.
- 23. Carnevale R, Pignatelli P, Di Santo S, et al. Atorvastatin inhibits oxidative stress via adiponectin-mediated NADPH oxidase down-regulation in hypercholesterolemic patients. Atherosclerosis. 2010;213(1):225-34.
- 24. Tolba MF, Azab SS, Khalifa AE, et al. Caffeic acid phenethyl ester, a promising component of propolis with a plethora of biological activities: a review on its anti-inflammatory, neuroprotective, hepatoprotective, and cardioprotective effects. IUBMB Life. 2013;65(8):699-709.
- 25. Akgun B, Ozturk S, Artas G, et al. Effects of Intrathecal Caffeic Acid Phenethyl Ester (CAPE) on IL-6 and TNF-α Levels and Local Inflammatory Responses in Spinal Cord Injuries. Turk Neurosurg. 2018;28(4):625-9.
PROTECTIVE EFFECT OF CAFFEIC ACID PHENETHYL ESTER AGAINST MYOPATHY INDUCED BY ATORVASTIN AND ROSUVASTATIN
Abstract
OBJECTIVE: Due to the fact that statins cause myopathy in some patients, the patient's compliance with the treatment decreases, and the treatment is interrupted or drug is changed. In this study, oxidative stress and inflammation, two conditions in which statins can cause myopathy, were studied and the protective role of Caffeic acid phenethyl ester (CAPE) was tested experimentally.
MATERIAL AND METHODS: Rhabdomyosarcoma (RD) cell lines were used in the study. Cells were divided into 6 groups as control, atorvastatin, rosuvastatin, CAPE, atorvastatin+CAPE and rosuvastatin+CAPE. Total Antioxidant Capacity (TAC), Total Oxidative Capacity (TOC), and Oxidative Stress Index (OSI) analyzes were made spectrophotometrically; Interleukin 6 (IL-6) levels were demonstrated both at the protein level by ELISA and at the level of mRNA expression by real time PCR.
RESULTS: OSI, which was 1739 in the control group, increased to 3814 with atorvastatin application and decreased to 2109 with the combination of atorvastatin and CAPE. There was no change in OSI levels in Rosuvastatin and Rosuvastatin and CAPE combination compared to the control group. While IL-6 mRNA expression levels were found to be similar to the control group in the atorvastin group, an increase of 2.369 times was observed in the Rosuvastatin group compared to the control group. As a result of the combination of rosuvastatin with CAPE, it was determined that IL-6 mRNA expression levels were reduced to the level of the control group.
CONCLUSIONS: In this study, it was observed that atorvastatin triggered oxidative stress in RD cell lines, while rosuvastatin increased the expression level of IL-6 mRNA and paved the way for the process leading to proinflammation. The combination of CAPE was found to be functional in suppressing oxidative stress caused by atorvastatin and inflammation caused by rosuvastatin. In this regard, it has been shown that the combination of atorvastatin and rosuvastatin with CAPE may have positive results for the benefit of the patient on muscle damage caused by statins.
Project Number
TDK-2021-7117
References
- 1. Stroes ES, Thompson PD, Corsini A, et al. European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012-22.
- 2. Nielsen SF, Nordestgaard BG. Statin use before diabetes and risk of microvascular disease: a nation wide nested matched study. Lancet Diabet Endocrinol. 2014;2:894-900.
- 3. Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-relatedmortality. N Engl J Med. 2012;367:1792-802.
- 4. Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137:581–5.
- 5. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundamental & Clinical Pharmacology. 2005;19:117-25.
- 6. Du Souich P, Roederer G, Dufour R. Myotoxicity of statins: Mechanism of action. Pharmacol Ther. 2017;175:1-16.
- 7. Zhang P, Tang Y, Li NG, Zhu Y, Duan JA. Bioactivity and chemical synthesis of caffeic acid phenethyl ester and its derivatives. Molecules. 2014;19(10):16458-76.
- 8. Li D, Wang X, Huang Q, Li S, et al. Cardioprotection of CAPE-oNO 2 against myocardial ischemia/reperfusion induced ROS generation via regulating the SIRT1/eNOS/NF-κB pathway in vivo and in vitro. Redox Biol. 2018;15:62-73.
- 9. Parlakpinar H, Sahna E, Acet A, Mizrak B, Polat A. Protective effect of caffeic acid phenethyl ester (CAPE) on myocardial ischemia-reperfusion-induced apoptotic cell death. Toxicology. 2005;209(1):1-14.
- 10. Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods. 1983;65:55–63.
- 11. Erel Ö. A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem. 2004;37(2):112-9.
- 12. Erel Ö. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005;38(12):1103-11.
- 13. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29(9):45.
- 14. Akgun B, Ozturk S, Artas G, Erol FS. Effects of Intrathecal Caffeic Acid Phenethyl Ester (CAPE) on IL-6 and TNF-α Levels and Local Inflammatory Responses in Spinal Cord Injuries. Turk Neurosurg. 2018;28(4):625-9.
- 15. Yiğit U, Kırzıoğlu FY, Uğuz AC, Nazıroğlu M, Özmen Ö. Is caffeic acid phenethyl ester more protective than doxycycline in experimental periodontitis? Arch Oral Biol. 2017;81:61-8.
- 16. Gazzerro P, Proto MC, Gangemi G, et al. Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol Rev. 2012;64(1):102-46.
- 17. Tomaszewski M, Stępień KM, Tomaszewska J, Czuczwar SJ. Statin-induced myopathies. Pharmacol Rep. 2011;63(4):859-66.
- 18. Bouitbir J, Charles AL, Echaniz-Laguna A, et al. Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a 'mitohormesis' mechanism involving reactive oxygen species and PGC-1. Eur Heart J. 2012;33(11):1397-407.
- 19. Kilit C, Koçak FE, Kilit TP. Comparison of the effects of high-dose atorvastatin and high-dose rosuvastatin on oxidative stress in patients with acute myocardial infarction: A pilot study. Turk Kardiyol Dern Ars. 2017;45(3): 235-43.
- 20. Koksal M, Eren MA, Turan MN, Sabuncu T. The effects of atorvastatin and rosuvastatin on oxidative stress in diabetic patients. Eur J Intern Med. 2011;22(3):249-53.
- 21. Yang RL, Shi YH, Hao G, et al. Increasing Oxidative Stress with Progressive Hyperlipidemia in Human: Relation between Malondialdehyde and Atherogenic Index. J Clin Biochem Nutr. 2008;43(3):154-8.
- 22. Klafke JZ, da Silva MA, Panigas TF, et al. Effects of Campomanesia xanthocarpa on biochemical, hematological and oxidative stress parameters in hypercholesterolemic patients. J Ethnopharmacol. 2010;127(2):299-305.
- 23. Carnevale R, Pignatelli P, Di Santo S, et al. Atorvastatin inhibits oxidative stress via adiponectin-mediated NADPH oxidase down-regulation in hypercholesterolemic patients. Atherosclerosis. 2010;213(1):225-34.
- 24. Tolba MF, Azab SS, Khalifa AE, et al. Caffeic acid phenethyl ester, a promising component of propolis with a plethora of biological activities: a review on its anti-inflammatory, neuroprotective, hepatoprotective, and cardioprotective effects. IUBMB Life. 2013;65(8):699-709.
- 25. Akgun B, Ozturk S, Artas G, et al. Effects of Intrathecal Caffeic Acid Phenethyl Ester (CAPE) on IL-6 and TNF-α Levels and Local Inflammatory Responses in Spinal Cord Injuries. Turk Neurosurg. 2018;28(4):625-9.
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Clinical Sciences |
| Journal Section | Articles |
| Authors | |
| Project Number | TDK-2021-7117 |
| Publication Date | July 13, 2023 |
| Acceptance Date | November 28, 2022 |
| Published in Issue | Year 2023 Volume: 24 Issue: 3 |
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